Beyond traditional cures

Anyone familiar with the events occurring inside living cells must feel a sense of awe at the complexities involved. Given the vast number of activities that need to be coordinated in every cell, it is not surprising that malfunctions occasionally arise.

Cancer is a prominent example of a disease that arises from such abnormalities in cell function. If current trends continue, almost half the population of the US will eventually develop cancer, making it the second-leading cause of death after cardiovascular disease. Although our understanding of the molecular and genetic defects that lead to cancer is not yet complete, enormous progress has been made in recent years and there is reason to believe that our growing understanding of this dreaded disease will eventually allow it to be brought under control.

People diagnosed with cancer have various treatment options that depend both on the type of cancer involved and how far it has spread. The most common approach involves surgery to remove the primary tumour followed (if necessary) by radiation therapy and/or chemotherapy to destroy any remaining cancer cells.

One problem with drugs and radiation therapy is that they are toxic to normal dividing cells as well as to cancer cells. When cancer arises in a tissue whose growth requires a specific hormone, it may be treated in a less toxic fashion using drugs that block the action of that particular hormone. For example, many breast cancers require estrogen for their growth. Estrogens exert their effects by binding to nuclear receptor proteins that activate the expression of specific genes. The drug tamoxifen, a common treatment for breast cancer, binds to estrogen receptors in place of estrogen and prevents the receptors from being activated.

The use of surgery, radiation, or chemotherapy - either in isolation or in various combinations - can cure or significantly prolong survival times for many types of cancer, especially when the disease is diagnosed early. However, some of the more aggressive cancers (such as those involving the lung, pancreas or liver) are difficult to control in these ways, and current approaches are not very successful with cancers diagnosed in their advan-ced stages. In trying to find more effective ways to treat such cancers, scientists have been looking for "magic bullets" that selectively seek out and destroy cancer cells without damaging normal cells in the process.

One strategy for introducing such selectivity into cancer treatment is to exploit the ability of the immune system to recognise cancer cells. This approach, called immunotherapy, was first proposed in the 1800s after doctors noticed that tumours occasionally regress in people who develop bacterial infections. Since infections trigger an immune response, subsequent attempts were made to build on this observation by utilising live or dead bacteria to provoke the immune system of cancer patients. Although the approach has not worked as well as initially hoped, some success has been seen with Bacillus Calmette-Guerin - a bacterial strain that does not cause disease but elicits a strong immune response at the site where it is introduced into the body. BCG is useful in treating early stage bladder cancers that are localised to the bladder wall. After the primary tumour has been surgically removed, inserting BCG into the bladder elicits a prolonged activation of immune cells that in turn leads to lower rates of cancer recurrence.

While it demonstrates the potential usefulness of immune stimulation, BCG must be administered directly into the bladder to provoke an immune response at the primary tumour site. To treat cancers that have already metastasised to unknown locations, an immune response must be stimulated wherever cancer cells might have travelled. Normal proteins that the body produces to stimulate the imm-une system are sometimes useful for this purpose. Interferon alpha and interleukin-2 (IL-2) are two such proteins that have been successfully used as drugs for treating certain types of cancer. Attempts are also underway to develop vaccines that introduce cancer-cell antigens into patients to stimulate the immune system to attack cancer cells.

Another way of using the immune system to fight cancer is with antibodies, which are proteins whose ability to recognise and bind to target molecules with extraordinary specificity makes them ideally suited to serve as agents that selectively attack cancer cells.

Until the early 1980s, the development of new cancer drugs focused largely on agents that disrupt DNA and interfere with cell division. While such drugs are useful in treating cancer, their effectiveness is often limited by toxic effects on normal dividing cells. In the last two decades, the identification of individual genes that are mutated or abnormally expressed in cancer cells has created a new possibility-molecular targeting-in which drugs are designed to specifically target those proteins that are critical to the cancer cell.

One approach for molecular targeting involves the use of monoclonal (pure) antibodies that bind to proteins involved in the signalling pathways that drive cancer cell proliferation. The first antibody to be approved for use in cancer patients, called herceptin, binds to and inactivates the growth factor receptor produced by the ERBB2 gene. About 25 per cent of all breast and ovarian cancers have amplified ERBB2 genes that produce excessive amounts of this receptor. When individuals with such cancers are treated with herceptin, the herceptin antibody binds to the receptor and inhibits its ability to stimulate cell proliferation, thereby slowing or stopping tumour growth.

An alternative way of targeting molecules for inactivation, called rational drug design, involves the laboratory synthesis of small molecule inhibitors that are designed to inactivate specific target proteins. One of the first anti-cancer drugs to be developed in this way was gleevec. It is a small molecule that binds to and inhibits an abnormal tyrosine kinase produced by the BCR-ABL oncogene, which arises from the fusion of two unrelated genes and produces a structurally abnormal tyrosine kinase that represents an ideal drug target because it is produced only by cancer cells. The effectiveness of gleevec as a treatment for early stage myelogenous leukemia is quite striking. More than half of the patients treated with gleevec have no signs of the cancer six months after treatment, a response rate that is 10 times better than that observed with earlier treatments.

Based on the encouraging results obtained with herceptin and gleevec, dozens of other drugs that utilise the principle of molecular targeting are currently under development. Tyrosine kinases and growth factor receptors (the targets for gleevec and herceptin) are just two of many potential targets for such drugs.

(The writer is associate professor, head, department of botany, Ananda Mohan College, Kolkata, and also fellow, Botanical Society of Bengal)